Faculty Collaboration Database

Role of interferon regulatory factor-1 in double-stranded RNA-induced iNOS expression by mouse islets. J Biol Chem 2002 Jan 04;277(1):359-65

Date

11/06/2001

Pubmed ID

11694524

DOI

10.1074/jbc.M109819200

Scopus ID

2-s2.0-0037016711 (requires institutional sign-in at Scopus site)   34 Citations

Abstract

Environmental factors, such as viral infection, have been implicated as potential triggering events leading to the initial destruction of pancreatic beta cells during the development of autoimmune diabetes. Double-stranded RNA (dsRNA), the active component of a viral infection that stimulates antiviral responses in infected cells, has been shown in combination with interferon-gamma (IFN-gamma) to stimulate inducible nitric oxide synthase (iNOS) expression and nitric oxide production and to inhibit beta cell function. Interferon regulatory factor-1 (IRF-1), the activation of which is induced by dsRNA, viral infection, and IFN-gamma, regulates the expression of many antiviral proteins, including PKR, type I IFN, and iNOS. In this study, we show that IRF-1 is not required for dsRNA + IFN-gamma-stimulated iNOS expression and nitric oxide production by mouse islets. In contrast to islets, dsRNA + IFN-gamma fails to induce iNOS expression or nitric oxide production by macrophages isolated from IRF-1(-/-) mice; however, dsRNA + IFN-gamma induces similar levels of IL-1 release by macrophages isolated from both IRF-1(-/-) and IRF-1(+/+) mice. Importantly, we show that dsRNA- or dsRNA + IFN-gamma-stimulated IRF-1 expression by mouse islets and peritoneal macrophages is independent of PKR. These results indicate that IRF-1 is required for dsRNA + IFN-gamma-induced iNOS expression and nitric oxide production by mouse peritoneal macrophages but not by mouse islets. These findings suggest that dsRNA + IFN-gamma stimulates iNOS expression by two distinct PKR-independent mechanisms; one that is IRF-1-dependent in macrophages and another that is IRF-1-independent in islets.

Author List

Blair LA, Maggi LB Jr, Scarim AL, Corbett JA

Author

John A. Corbett PhD Chair, Professor in the Biochemistry department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Cells, Cultured
Cycloheximide
DNA-Binding Proteins
Female
Interferon Regulatory Factor-1
Interferon-gamma
Interleukin-1
Islets of Langerhans
Macrophages, Peritoneal
Male
Mice
Nitric Oxide
Nitric Oxide Synthase
Nitric Oxide Synthase Type II
Phosphoproteins
RNA, Double-Stranded
RNA, Messenger
eIF-2 Kinase